Winfried Rief

Genome wide association (GWA) study for early onset extreme obesity supports the role of fat mass and obesity associated gene (FTO) variants.

Background Obesity is a major health problem. Although heritability is substantial, genetic mechanisms predisposing to obesity are not very well understood. We have performed a genome wide association study (GWA) for early onset (extreme) obesity. Methodology/Principal Findings a) GWA (Genome-Wide Human SNP Array 5.0 comprising 440,794 single nucleotide polymorphisms) for early onset extreme obesity based on 487 extremely obese young German individuals and 442 healthy lean German controls; b) confirmatory analyses on 644 independent families with at least one obese offspring and both parents. We aimed to identify and subsequently confirm the 15 SNPs (minor allele frequency ≥10%) with the lowest p-values of the GWA by four genetic models: additive, recessive, dominant and allelic. Six single nucleotide polymorphisms (SNPs) in FTO (fat mass and obesity associated gene) within one linkage disequilibrium (LD) block including the GWA SNP rendering the lowest p-value (rs1121980; log-additive model: nominal p = 1.13×10−7, corrected p = 0.0494; odds ratio (OR)CT 1.67, 95% confidence interval (CI) 1.22–2.27; ORTT 2.76, 95% CI 1.88–4.03) belonged to the 15 SNPs showing the strongest evidence for association with obesity. For confirmation we genotyped 11 of these in the 644 independent families (of the six FTO SNPs we chose only two representing the LD bock). For both FTO SNPs the initial association was confirmed (both Bonferroni corrected p<0.01). However, none of the nine non-FTO SNPs revealed significant transmission disequilibrium. Conclusions/Significance Our GWA for extreme early onset obesity substantiates that variation in FTO strongly contributes to early onset obesity. This is a further proof of concept for GWA to detect genes relevant for highly complex phenotypes. We concurrently show that nine additional SNPs with initially low p-values in the GWA were not confirmed in our family study, thus suggesting that of the best 15 SNPs in the GWA only the FTO SNPs represent true positive findings.

Somatization Symptoms and Hypochondriacal Features in the General Population

Objective The principal goal of this study is to examine the base rates of somatoform symptoms and of hypochondriacal features in the general population. Methods A representative sample of 2050 persons in Germany was examined by use of screening for somatoform symptoms and the Whiteley Index. Results The most frequent somatoform symptoms were back pain, joint pain, pain in extremities, and headache, as well as abdominal symptoms (bloating or intolerance of several foods) and cardiovascular symptoms (palpitation). People reported a mean of two somatization symptoms of DSM-IV somatization disorder (SD) during the prior 2 years. Strong age and medium gender effects were found for most somatoform symptoms, as well as for composite indices. However, the sex ratio suggested in DSM-IV for SD seems to be an overestimation. Hypochondriacal features showed only small sex differences but, again, pronounced age effects. In contrast to low rates for SD, the base rates for somatization and hypochondriacal features were high and represented the health care relevance of subthreshold syndromes. Conclusion We present base rates of hypochondriacal and somatization features that may be important facets in the development of classification criteria and in the interpretation of health care expenditure.

Two new Loci for body-weight regulation identified in a joint analysis of Genome-Wide Association Studies for Early-Onset Extreme Obesity in French and German Study Groups

Meta-analyses of population-based genome-wide association studies (GWAS) in adults have recently led to the detection of new genetic loci for obesity. Here we aimed to discover additional obesity loci in extremely obese children and adolescents. We also investigated if these results generalize by estimating the effects of these obesity loci in adults and in population-based samples including both children and adults. We jointly analysed two GWAS of 2,258 individuals and followed-up the best, according to lowest p-values, 44 single nucleotide polymorphisms (SNP) from 21 genomic regions in 3,141 individuals. After this DISCOVERY step, we explored if the findings derived from the extremely obese children and adolescents (10 SNPs from 5 genomic regions) generalized to (i) the population level and (ii) to adults by genotyping another 31,182 individuals (GENERALIZATION step). Apart from previously identified FTO, MC4R, and TMEM18, we detected two new loci for obesity: one in SDCCAG8 (serologically defined colon cancer antigen 8 gene; p = 1.85×10−8 in the DISCOVERY step) and one between TNKS (tankyrase, TRF1-interacting ankyrin-related ADP-ribose polymerase gene) and MSRA (methionine sulfoxide reductase A gene; p = 4.84×10−7), the latter finding being limited to children and adolescents as demonstrated in the GENERALIZATION step. The odds ratios for early-onset obesity were estimated at ∼1.10 per risk allele for both loci. Interestingly, the TNKS/MSRA locus has recently been found to be associated with adult waist circumference. In summary, we have completed a meta-analysis of two GWAS which both focus on extremely obese children and adolescents and replicated our findings in a large followed-up data set. We observed that genetic variants in or near FTO, MC4R, TMEM18, SDCCAG8, and TNKS/MSRA were robustly associated with early-onset obesity. We conclude that the currently known major common variants related to obesity overlap to a substantial degree between children and adults.

The prevalence of body dysmorphic disorder: a population-based survey

BACKGROUND Body dysmorphic disorder (BDD) is a highly distressing and impairing disorder characterized by a preoccupation with imagined or slight physical defects in appearance. Well designed studies on its prevalence and on base rates for diagnostic criteria are rare. Therefore this study aimed to reveal prevalence rates of BDD in the general population and to examine clinical features associated with BDD. METHOD Of 4152 selected participants 2552, aged 14-99 years, participated in this German nationwide survey. Participants were carefully selected to ensure that the sample was representative; they were visited by a study assistant who provided instructions and help if needed. Participation rate was 62.3%. DSM-IV criteria for BDD, as well as subthreshold features (e.g. individuals who consider some part(s) of their body as ugly or disfigured, but do not fulfill all BDD criteria) were examined. We also assessed suicidal ideation associated with the belief of having an ugly body part, as well as the desire for cosmetic surgery. Furthermore, somatization symptoms were assessed. RESULTS The prevalence of current BDD was 1.7% (CI 1.2-2.1%). Individuals with BDD reported higher rates of suicidal ideation (19% v. 3%) and suicide attempts due to appearance concerns (7% v. 1%) than individuals who did not meet criteria for BDD. Somatization scores were also increased in individuals with BDD, relative to those without. BDD was associated with lower financial income, lower rates of living with a partner, and higher rates of unemployment. CONCLUSIONS Our study shows that self-reported BDD is relatively common and associated with significant morbidity.

A classification of chronic pain for ICD-11

Chronic pain has been recognized as pain that persists past normal healing time5 and hence lacks the acute warning function of physiological nociception.35 Usually pain is regarded as chronic when it lasts or recurs for more than 3 to 6 months.29 Chronic pain is a frequent condition, affecting an estimated 20% of people worldwide6,13,14,18 and accounting for 15% to 20% of physician visits.25,28 Chronic pain should receive greater attention as a global health priority because adequate pain treatment is a human right, and it is the duty of any health care system to provide it.4,13 The current version of the International Classification of Diseases (ICD) of the World Health Organization (WHO) includes some diagnostic codes for chronic pain conditions, but these diagnoses do not reflect the actual epidemiology of chronic pain, nor are they categorized in a systematic manner. The ICD is the preeminent tool for coding diagnoses and documenting investigations or therapeutic measures within the health care systems of many countries. In addition, ICD codes are commonly used to report target diseases and comorbidities of participants in clinical research. Consequently, the current lack of adequate coding in the ICD makes the acquisition of accurate epidemiological data related to chronic pain difficult, prevents adequate billing for health care expenses related to pain treatment, and hinders the development and implementation of new therapies.10,11,16,23,27,31,37 Responding to these shortcomings, the International Association for the Study of Pain (IASP) contacted the WHO and established a Task Force for the Classification of Chronic Pain. The IASP Task Force, which comprises pain experts from across the globe,19 has developed a new and pragmatic classification of chronic pain for the upcoming 11th revision of the ICD. The goal is to create a classification system that is applicable in primary care and in clinical settings for specialized pain management. A major challenge in this process was finding a rational principle of classification that suits the different types of chronic pain and fits into the general ICD-11 framework. Pain categories are variably defined based on the perceived location (headache), etiology (cancer pain), or the primarily affected anatomical system (neuropathic pain). Some diagnoses of pain defy these classification principles (fibromyalgia). This problem is not unique to the classification of pain, but exists throughout the ICD. The IASP Task Force decided to give first priority to pain etiology, followed by underlying pathophysiological mechanisms, and finally the body site. Developing this multilayered classification was greatly facilitated by a novel principle of assigning diagnostic codes in ICD-11, termed “multiple parenting.” Multiple parenting allows the same diagnosis to be subsumed under more than 1 category (for a glossary of ICD terms refer to Table ​Table1).1). Each diagnosis retains 1 category as primary parent, but is cross-referenced to other categories that function as secondary parents. Table 1 Glossary of ICD-11 terms. The new ICD category for “Chronic Pain” comprises the most common clinically relevant disorders. These disorders were divided into 7 groups (Fig. ​(Fig.1):1): (1) chronic primary pain, (2) chronic cancer pain, (3) chronic posttraumatic and postsurgical pain, (4) chronic neuropathic pain, (5) chronic headache and orofacial pain, (6) chronic visceral pain, and (7) chronic musculoskeletal pain. Experts assigned to each group are responsible for the definition of diagnostic criteria and the selection of the diagnoses to be included under these subcategories of chronic pain. Thanks to Bedirhan Ustun and Robert Jakob of the WHO, these pain diagnoses are now integrated in the beta version of ICD-11 (http://id.who.int/icd/entity/1581976053). The Task Force is generating content models for single entities to describe their clinical characteristics. After peer review overseen by the WHO Steering Committee,39 the classification of chronic pain will be voted into action by the World Health Assembly in 2017. Figure 1 Organizational chart of Task Force, IASP, and WHO interactions. The IASP Task Force was created by the IASP council and its scope defined in direct consultation of the chairs (R.D.T. and W.R.) with WHO representatives in 2012. The Task Force reports to ... 2. Classification of chronic pain Chronic pain was defined as persistent or recurrent pain lasting longer than 3 months. This definition according to pain duration has the advantage that it is clear and operationalized. Optional specifiers for each diagnosis record evidence of psychosocial factors and the severity of the pain. Pain severity can be graded based on pain intensity, pain-related distress, and functional impairment. 2.1. Chronic primary pain Chronic primary pain is pain in 1 or more anatomic regions that persists or recurs for longer than 3 months and is associated with significant emotional distress or significant functional disability (interference with activities of daily life and participation in social roles) and that cannot be better explained by another chronic pain condition. This is a new phenomenological definition, created because the etiology is unknown for many forms of chronic pain. Common conditions such as, eg, back pain that is neither identified as musculoskeletal or neuropathic pain, chronic widespread pain, fibromyalgia, and irritable bowel syndrome will be found in this section and biological findings contributing to the pain problem may or may not be present. The term “primary pain” was chosen in close liaison with the ICD-11 revision committee, who felt this was the most widely acceptable term, in particular, from a nonspecialist perspective.

Psychological treatments for fibromyalgia: A meta-analysis

&NA; The aims of the present analysis were to investigate the short‐ and long‐term efficacies and treatment moderators of psychological interventions for fibromyalgia. A literature search using PubMed, PsychINFO, the Cochrane Library, and manual searches identified 23 eligible studies including 30 psychological treatment conditions and 1396 patients. Meta‐analytic integration resulted in a significant but small effect size for short‐term pain reduction (Hedgess g = 0.37, 95% confidence interval (CI): 0.27–0.48) and a small‐to‐medium effect size for long‐term pain reduction over an average follow‐up phase of 7.4 months (Hedgess g = 0.47, 95% CI: 0.3–0.65) for any psychological intervention. Psychological treatments also proved effective in reducing sleep problems (Hedgess g = 0.46, 95% CI: 0.28–0.64), depression (Hedgess g = 0.33, 95% CI: 0.20–0.45), functional status (Hedgess g = 0.42, 95% CI: 0.25–0.58), and catastrophizing (Hedgess g = 0.33, 95% CI: 0.17–0.49). These effects remained stable at follow‐up. Moderator analyses revealed cognitive‐behavioral treatment to be significantly better than other psychological treatments in short‐term pain reduction (Hedgess g = 0.60, 95% CI: 0.46–0.76). Higher treatment dose was associated with better outcome. Publication‐bias analyses demonstrated that the effect sizes were robust. The results suggest that the effects of psychological treatments for fibromyalgia are relatively small but robust and comparable to those reported for other pain and drug treatments used for this disorder. Cognitive‐behavioral therapy was associated with the greatest effect sizes.

Cognitive Aspects of Hypochondriasis and the Somatization Syndrome

The aim of this study was to evaluate whether specific cognitive aspects are present in patients suffering from somatoform disorders. With a sample of 493 patients from a center for behavioral medicine, the authors evaluated a questionnaire assessing typical cognitions concerning body perception, illness behavior, and health. The authors further examined 225 participants, including patients with a somatization syndrome, patients with somatization syndrome and additional hypochondriasis, patients with hypochondriasis, patients with other mental disorders (clinical control group), and nonclinical controls. The results showed that not only patients with hypochondriasis but also patients with somatization syndrome had cognitive concerns and assumptions that were specific for the disorder. These patients had a self-concept of being weak and unable to tolerate stress. A catastrophizing interpretation of minor bodily complaints found in hypochondriacal patients in earlier studies was also found for patients with multiple somatization symptoms.

Psychobiological perspectives on somatoform disorders

Common physical symptoms such as abdominal pain, headache, back pain and dizziness play a major role for the health care system. Existing models for the development and maintenance of these symptoms emphasize a vicious circle with cognitive-perceptual, behavioral, and psychobiological components. In this manuscript, we present examples of psychobiological factors that might contribute to somatoform disorders. We emphasize that somatoform symptoms are not strictly mental events, but are associated with a diversity of biological processes. The possible role of the endocrine and immune system, amino acids and neurotransmitters, but also physiological activation and cerebral activity is exemplified. These approaches are categorized using a model of perception and filtering of bodily signals. Studies are needed that combine the investigation of different biological systems with assessments of psychological variables in longitudinal trials, but also experimental investigations in humans examining the interaction of behavior changes, biological variations, and body perception are still rare.

Meta-analysis of the placebo response in antidepressant trials

UNLABELLED Improvements in placebo groups of antidepressant trials account for a major part of the expected drug effects. We aimed to determine overall effect sizes of placebo and drug effects in antidepressant trials, and to analyze whether the placebo effect in antidepressant trials also occurs for patient self-perception, general psychopathology, and quality of life. METHODS Search terms covered different variants of pharmacotherapy for patients with depressive disorders from January 1980 to December 2005 in the databases Medline/Pubmed, PsychInfo and CENTRAL, a.o. We included RCTs with a placebo group and an antidepressant group in people with depression. RESULTS We computed within group effect sizes for several outcome variables and integrated them using random-effect models. A total of 96 studies were included. Mean effect size in the placebo group for primary outcome variables was d=1.69 (95% CI=1.54-1.84) compared to 2.50 in the drug group (95% CI=2.30-2.69). There was a major difference between placebo effect sizes assessed with observer ratings (d=1.85, 95% CI=1.69-2.01) versus patient self-perception (d=0.67; 95% CI=0.49-0.85). The effect sizes in placebo groups in 2005 were more than twice as great as those in 1980, but only for observer ratings, not for patient self-ratings. The result was partly due to increased homogeneity of samples of recently published trials. CONCLUSIONS The placebo effect accounted for 68% of the effect in the drug groups. Whereas clinical trials need to control the placebo effect, clinical practice should attempt to use its full power.

The Association of a SNP Upstream of INSIG2 with Body Mass Index is Reproduced in Several but Not All Cohorts

A SNP upstream of the INSIG2 gene, rs7566605, was recently found to be associated with obesity as measured by body mass index (BMI) by Herbert and colleagues. The association between increased BMI and homozygosity for the minor allele was first observed in data from a genome-wide association scan of 86,604 SNPs in 923 related individuals from the Framingham Heart Study offspring cohort. The association was reproduced in four additional cohorts, but was not seen in a fifth cohort. To further assess the general reproducibility of this association, we genotyped rs7566605 in nine large cohorts from eight populations across multiple ethnicities (total n = 16,969). We tested this variant for association with BMI in each sample under a recessive model using family-based, population-based, and case-control designs. We observed a significant (p < 0.05) association in five cohorts but saw no association in three other cohorts. There was variability in the strength of association evidence across examination cycles in longitudinal data from unrelated individuals in the Framingham Heart Study Offspring cohort. A combined analysis revealed significant independent validation of this association in both unrelated (p = 0.046) and family-based (p = 0.004) samples. The estimated risk conferred by this allele is small, and could easily be masked by small sample size, population stratification, or other confounders. These validation studies suggest that the original association is less likely to be spurious, but the failure to observe an association in every data set suggests that the effect of SNP rs7566605 on BMI may be heterogeneous across population samples.